Abstract A major challenge in the treatment of neurological diseases is the elaborate and diffuse nature of neural circuits, where physically proximal neurons are engaged in functionally different pathways. The ability to target neurons based on function, rather than location, is critical to improving treatments for disease. In Parkinson's disease, improved treatments have been driven by the discovery of cell type diversity in the striatum, providing access to functionally opposing circuits: the direct and indirect pathways. However, with the exception of neuronal diversity in the striatum, all other downstream nuclei in the basal ganglia are depicted as homogeneous relay nuclei, an oversimplification whose limits are increasingly apparent as techniques to study circuit function become more sophisticated. Recently, my lab has pioneered the use of transgenic mouse lines to subdivide neurons in the external globus pallidus (GPe) into subpopulations that differ in anatomy and electrophysiological properties. Leveraging tools to optogenetically manipulate these genetic subpopulations, we are now in position to discover their contributions to behavior. In a recent study, we found that optogenetic interventions targeted to particular subpopulations in the GPe (but not global stimulation of the entire nucleus) restores motor function in acutely dopamine depleted mice, and the effects persisted for hours after stimulation. This finding challenges long-standing models of circuit organization in the basal ganglia and has relevance for PD, where current interventions provide only transient relief of motor symptoms that rapidly return once stimulation stops. Experiments in this proposal will test the ability of GPe interventions to rescue movement in a chronic dopamine depletion model (Aim 1) and will elucidate the pathways through which GPe subpopulations mediate their effects (Aim 2). Aim 1, will use optogenetics and in vivo recordings to assess the impact of modulating genetically-defined neuronal subpopulations on local circuit dynamics in the GPe and their effects on behavior. Specifically, we will test the hypothesis that recovered movements following optogenetic stimulation are goal-directed and restore the ability of mice to seek out food, social interactions, and avoid anxiety-provoking environments. In Aim 2, we will use in vivo recordings, coupled with viral-assisted circuit mapping, to elucidate the pathways through which neuronal subpopulations in the GPe exert their prokinetic effects on movement. Our preliminary data suggest that therapeutic interventions share a common mechanism of reversing pathological firing patterns in the substantia nigra reticulata (SNr), the primary basal ganglia output nucleus in rodents. Our proposed experiments will determine whether this effect is mediated by direct projections of GPe neurons to the SNr, or whether it is mediated through a disynaptic pathway involving the subthalamic nucleus (STN). Combined, results from these studies will elucidate the pathways and circuit mechanisms responsible for long-lasting motor rescue in dopamine depleted mice and will revise long-standing models of indirect pathway dysfunction in disease.